: Spinal adenosine modulator: enduring anti-inflammatory action in neuropathic pain Project Summary/Abstract This application addresses broad Challenge Area (15) Translational Science &specific Challenge Topic 15- NS-103 Demonstration of "proof-of-concept" for a new therapeutic approach in a neurological disease. Neuropathic pain remains intractable despite treatment with currently available therapeutic agents. Therefore, it is necessary to identify novel pharmacotherapeutics that can effectively attenuate neuropathic pain. Activation of microglia and astrocytes (glial cells) plays a crucial role in chronic pain states, including neuropathic pain, by chronically inducing the release of neuroexcitatory substances such as pro-inflammatory cytokines and chemokines. This pro-inflammatory milieu surrounds neurons, helping to maintain the hyperexcitable state of neurons associated with chronic pain states. An optimal therapeutic would "reset" these chronically activated glial cells to an overtly anti-inflammatory state, thus returning the neuronal excitation to basal levels. Such a drug, were it to exist, would be predicted to reduce neuropathic pain by removing the tonic "drive" to the pain system provided by glial activation. We believe that we have identified such agents;namely, adenosine 2A (A2A) agonists. Mechanistically, these are agonists at one adenosine receptor subtype. Adenosine is a purine that exerts its effects via four subtypes of G-protein coupled adenosine receptors (A1, A2A, A2B and A3). Adenosine 2A receptors are found on most tissues in the body including spinal cord neurons, microglia, astrocytes, endothelial cells and oligodendrocytes. The selective activation of the A2A receptor subtype is immunosuppressive, decreasing pro-inflammatory cytokines and increasing the powerful anti-inflammatory cytokine, interleukin-10 (IL-10). In addition, activation of A2A receptors reduces NMDA activation in primary sensory neurons. Preliminary data, using the chronic constriction injury (CCI) model, support that a single intrathecal injection of A2A agonists produces a remarkably enduring reversal of neuropathic pain of at least several weeks. In order to fully understand the impact of A2A agonists on chronic pain conditions, we are proposing to 1) thoroughly characterize the reversal in established neuropathic pain following a single versus multiple injections to ascertain if tolerance to the agonist's pain suppressive effects develops;and, 2) begin to characterize the cell types involved in the agonist's pain suppression. While the mechanism of action most likely includes a neuron-glia interaction, given the known role of glia in pain development and maintenance, our focus will be on glial changes, with neuronal changes assessed concurrently as time and funds allow. In addition, we will assess whether the persistent effect of the A2A agonist is specific to the A2A adenosine receptor or if modulating adenosine regulation via other adenosine receptors will produce the same effect. PUBLIC HEALTH RELEVANCE: NINDS Proposal: Spinal adenosine modulator: enduring anti-inflammatory action in neuropathic pain Project Narrative This proposal builds from our discovery that a single intrathecal administration of adenosine 2A (A2A) agonists produces a remarkably enduring reversal of neuropathic pain of at least several weeks, with evidence to date suggestive that such drugs may "reset" chronically activated spinal glial cells to an overtly anti-inflammatory state that suppresses pain. This project is aimed at providing the "proof-of-concept" for using A2A agonists as a new therapeutic approach for chronic pain.